tbuckley/cabot-search huggingface dataset:
Abstract B060: Investigating the role of ERphagy in pancreatic cancer
Authors: Sandra L. Vogt, Dafna Bar-Sagi
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) harbors mutations in KRAS in greater than 90% of cases and is characterized by a dense, fibrotic stroma that fosters the formation of a hypoxic, nutrient-poor tumor microenvironment. Tumor cells counteract these stresses through the hyperactivation of multiple nutrient scavenging pathways, including macropinoytosis and macroautophagy. Whereas the role of the latter in the regulation of PDAC growth has been extensively studied, much less is known about the role of endoplasmic reticulum (ER)-specific autophagy (ERphagy), a homeostatic mechanism involving ER membrane remodeling which promotes the clearance of misfolded protein aggregates, thereby supporting proteostasis. Using an ERphagy reporter system, we found that pancreatic cancer cells display mutant KRas-dependent suppression of ERphagy both at baseline and in the context of nutrient deprivation, which was partially dependent on the ER-resident receptor CCPG1. Furthermore, direct perturbation of the 26S proteasome with bortezomib enhanced ERphagy, suggesting that the attenuated ERphagy capacity in pancreatic cancer cells may reflect a greater dependence on proteasomal activity for the maintenance of proteostasis. Significantly, the knockdown of CCPG1 but not other ERphagy receptors augmented the growth-suppressive effects of bortezomib in vitro, an effect likely caused by unresolved proteotoxic stress. Overall, our findings implicate CCPG1-mediated ERphagy in pancreatic cancer cell survival and identify a targetable cell-intrinsic vulnerability that can potentiate the cytotoxic effects of bortezomib, which alone is clinically ineffective in treating PDAC. Citation Format: Sandra L. Vogt, Dafna Bar-Sagi. Investigating the role of ERphagy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B060.
Abstract C056: The prolyl isomerase PIN1 controls fibroblast state plasticity to impact pancreatic cancer
Authors: Ellen M. Langer, Vidhi Shah, Amy Farrell, Colin Daniel, Xiaoyan Wang, Kevin MacPherson, Brittany L. Allen-Petersen, Motoyuki Tsuda, Mara Sherman, Andrew Adey, Rosalie C. Sears
Journal: Cancer Research (2022)

Abstract Pancreatic cancer associated fibroblasts (CAFs) have been described to play multiple, often conflicting, roles to support or restrict tumor growth. Recent work suggests that heterogeneous differentiation states of fibroblasts contribute to these diverse functions and that reprogramming of fibroblast states can influence tumor outcomes. The impact of distinct fibroblast subpopulations on heterogeneous tumor development and growth, however, remain incompletely understood. PIN1 is a phosphorylation-directed prolyl isomerase that alters the conformation and, therefore, the function of many proteins. PIN1 is overexpressed in cancer and contributes to cancer cell-intrinsic pro-tumorigenic behaviors including cellular proliferation and migration. While its pro-tumor functions have generated interest in therapeutic targeting of PIN1 for cancer treatment, the direct effects of PIN1 inhibition on tumor-associated stromal phenotypes are poorly understood. We have found that PIN1 loss or inhibition results in decreased tumor growth in vivo in transplant or genetically engineered mouse models. Moreover, in syngeneic orthotopic allograft models in which loss of PIN1 is restricted to the tumor host, we observed that KPC tumor cells still have decreased growth, suggesting a critical role for PIN1 in the tumor microenvironment. We observed that PIN1 loss or inhibition in vivo was accompanied by decreased expression of alpha-SMA, a marker of myofibroblast-like CAFs, and have identified a role for PIN1 in the phenotypic and epigenetic response to TGF-beta, a major driver of the myCAF state. PIN1low pancreatic stellate cells or CAFs display altered cell morphology, decreased proliferation, decreased ECM deposition, as well as altered paracrine signaling to cancer cells and other stromal cells. We are currently using 2D co-cultures, heterotypic 3D bioprinted tissues, and in vivo mouse models to interrogate the molecular mechanisms by which PIN1 controls fibroblast phenotypes and functional impact of altering fibroblast state on tumor phenotypes and outcomes. In addition, we are defining PIN1-dependent mechanisms of crosstalk between neoplastic and non-neoplastic cells and are investigating the requirements for specific fibroblast states to support in vivo growth of heterogeneous pancreatic cancer cells. Citation Format: Ellen M. Langer, Vidhi Shah, Amy Farrell, Colin Daniel, Xiaoyan Wang, Kevin MacPherson, Brittany L. Allen-Petersen, Motoyuki Tsuda, Mara Sherman, Andrew Adey, Rosalie C. Sears. The prolyl isomerase PIN1 controls fibroblast state plasticity to impact pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C056.
Abstract IA019: Stromal-epithelial co-evolution and complicity in pancreas cancer
Authors: Sunil R. Hingorani
Journal: Cancer Research (2022)

Abstract The robust desmoplasia of PDA is its distinguishing feature and non-malignant components constitute the bulk of the tumor mass. This stromal reaction includes myofibroblasts, inflammatory fibroblasts, endothelial cells, pericytes, and various immune-cell subsets, all embedded within a dense and complex extracellular matrix (ECM). Dominated by non-malignant cells, the mutated epithelium must therefore combat, cooperate with, or coopt the surrounding cells and signaling processes in its microenvironment. It is proposed that an invasive PDA represents the coordinated evolution of malignant and non-malignant cells and mechanisms that subvert and repurpose the dictums of normal tissue composition, architecture, and physiology to foster tumorigenesis. The detailed kinetics and stepwise construction of the pancreas cancer neo-organ suggest that it is governed by a discrete set of organizing rules and principles – and repeated attempts to target its specific components reveal self-regulating mechanisms of resistance. Indeed, many of these cells arise and operate at the behest of oncogenic KRAS, the signature genetic mutation in PDA. These cells, in turn, support and shape the evolving malignancy. It is frequently debated in pancreas and other cancers whether the stroma is “good” or “bad”, tumor-constraining or tumor-promoting. However, because the stroma is neither static nor monolithic, the question is misguided. The stroma is more nuanced: some elements overtly accelerate, and others attenuate, disease progression but most of the cells and processes found in an evolving pancreas cancer are adaptive at some point during its development. In the end, these elements collectively conspire to create a drug- and immune-privileged sanctuary for PDA progression. To fully overcome the extraordinary resistance of this formidable cancer will require parsing the myriad interactions and interdependencies among the various stromal elements and the epithelial PDA cell. Understanding how to combine strategies against these distinct components and processes – which ones to target, in what order and for how long – will be critical, and perhaps necessary, for success and to avoid making matters worse. Citation Format: Sunil R. Hingorani. Stromal-epithelial co-evolution and complicity in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA019.
Abstract B044: Bromodomain and Extra-Terminal Protein inhibition decreases pancreatic cancer proliferation via MYC-independent pathways
Authors: Manjul Rana, Rita G. Kansal, Jie Fang, Benjamin T. Allen, Jun Yang, Evan S. Glazer
Journal: Cancer Research (2022)

Abstract Introduction: The bromodomain and extra-terminal (BET) protein family contains proteins which have evolutionarily conserved bromodomains (BRDs) that specifically recognize acetylated lysine residues on the histone tails of chromatin and regulate gene transcription. Deregulation of these BRD-containing proteins has been seen in carcinogenesis as they are also known to play role in the regulation of the cell-cycle and MYC oncogenes. BMS-986158 is an oral BET inhibitor which has been used in the clinical trials for both hematologic and advanced solid tumor cancers. We hypothesized that BET inhibition (BETi) decreases pancreatic ductal adenocarcinoma (PDA) proliferation. Methods: Pancreatic cancer cell lines and patient-derived cell-lines (PDCLs) were treated with 2.5 to 100nM BMS-986158 for 72 hours to study dose-response effect with Incucyte. We performed RNA-seq, qPCR, protein analysis, and flow cytometry to evaluate comprehensive changes and underlying mechanisms/pathways including epithelial to mesenchymal transition (EMT) and the cancer stem cell (CSC) phenotype. Various doses of BMS-986158 were used in PDCL and PDA patient-derived organoids (PDO) in combination with chemotherapy drug to evaluate combinational effects. Results: We found that BETi induced dose-dependent decrease in growth of PDA and PDCLs and induced cancer cell death. BETi demonstrated PDO growth inhibition which was enhanced when combined with gemcitabine and paclitaxel chemotherapy. Next, we found that BETi did not affect MYC expression but decreased expression of the SNAI1 (a mesenchymal marker) protein and increased E-cadherin protein expression in PDA cell line and PDO consistent with decreased activation of an EMT program. BETi also decreased expression of CD133, a marker of CSCs in PDO. BETi also induced G1/S Phase cell cycle arrest in PDA PDCLs. Furthermore, RNA-seq studies revealed that BETi treatment inhibits KRAS pathway and upregulates pathways involved in metabolism of lipids and lysosomal degradation. RNA-seq and qPCR demonstrated that GPX3 (glutathione peroxidase 3, a key protein in reactive oxygen species response) gene expression is upregulated in BETi treated samples. Conclusions: Thus, our data demonstrate that BETi through BMS-986158 is an additional therapy for inhibiting PDA growth through mechanisms that are independent of MYC pathway, inhibition of abnormal lipid metabolism and scavenging of reactive oxygen species. Citation Format: Manjul Rana, Rita G. Kansal, Jie Fang, Benjamin T. Allen, Jun Yang, Evan S. Glazer. Bromodomain and Extra-Terminal Protein inhibition decreases pancreatic cancer proliferation via MYC-independent pathways [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B044.
Abstract B014: TLR signaling coordinates SAA-dependent liver metastasis in pancreatic cancer
Authors: Jesse Lee, Meredith L. Stone, Hana Choi, Gregory L. Beatty
Journal: Cancer Research (2022)

Abstract Metastasis remains the primary cause of mortality in cancer. This is especially true in pancreatic ductal adenocarcinoma (PDAC) - where the liver is the most common site of metastasis and the 5-year overall survival rate for these patients has remained &amp;lt;3% for the past 20 years. Accumulating evidence shows a critical role for a niche microenvironment in the liver, termed the pro-metastatic niche, that supports metastatic seeding and outgrowth. Our previous work demonstrated that hepatocytes orchestrate the formation of this pro-metastatic niche during early tumorigenesis through the release of Serum Amyloid A1 and 2 (SAA). However, the mechanisms by which SAA directs formation of a pro-metastatic niche in the liver, and the impact of this niche on the fate of disseminating tumor cells (DTCs) seeding the liver, remain ill-defined. To begin to identify the cellular determinants of niche formation, we first analyzed the expression of SAA receptors within the normal liver and found predominant expression of receptors on the resident F4/80+ macrophages. This is in line with current published work as SAA is well characterized to control liver biology through toll-like receptors (TLRs) expressed by liver resident immune cells and hepatic stellate cells. Consistent with this, we also found that SAA is a specific, potent agonist of TLR2 in vitro. In tumor bearing mice we then found increased expression of TLR2 transcripts as well as an accumulation of TLR2+ inflammatory monocytes within the niche. Together, these findings suggested that SAA might form a pro-metastatic niche in the liver withough a TLR2-dependent mechanism. To test this, we next examined the livers of TLR2-/- tumor bearing mice and found a decrease in the expression of surrogate markers of the pro-metastatic niche. We also sought to determine a role for TLR2 in metastatic outgrowth. Using TLR2-/- mice in a model of PDAC with direct metastasis to the liver, we found significantly decreased metastatic burden and outgrowth in the liver. Analysis of micro-metastatic lesions in TLR2-/- tumor bearing mice also revealed that DTCs demonstrated molecular markers of cellular dormancy. Altogether, our findings suggest the evolution of an inflammatory mechanism within the niche wherein SAA may continue to signal through TLR2+ inflammatory monocytes, which then act to coordinate metastatic outgrowth. Future work aims to further elucidate the role of TLR2+ resident macrophages and monocytes in the formation of a pro-metastatic niche in the liver and in regulating metastatic outgrowth. Citation Format: Jesse Lee, Meredith L. Stone, Hana Choi, Gregory L. Beatty. TLR signaling coordinates SAA-dependent liver metastasis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B014.
Abstract B051: Design, synthesis, and in vitro evaluation of enedione derivatives as promising selective COPZ1 inhibitor
Authors: Allana Cristina F. Martins, Barbara M. Barbosa, Bretton Badenoch, Roberto S. Gomes
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is a disease with a rising incidence and low survival rate. Anticancer drugs are effective, but are not selective, leading to serious side effects, as pain, loss of taste bud, and hair loss. The available treatments are involved in target cell proliferation, but are ineffective against nonproliferating tumor cells, which could lead to a relapse. COPZ1 and its paralogous COPZ2 are involved in intracellular trafficking and autophagy. They were identified as essential for healthy and tumor cell survival. Both COPZ1 and COPZ2 are expressed in almost the same level in normal cells. Interestingly, in tumor cells, COPZ2 is downregulated. In normal cells, the simultaneous depletion of both COPZ1 and COPZ2 leads normal cells to apoptosis, but the depletion of only one of the proteins does not affect cell cycle. This fact led us to the hypothesis that tumor cells are COPZ1 dependent, and the inhibition of this protein could lead tumor cells to apoptosis selectively once COPZ2 is naturally downregulated. Once these proteins are involved in intracellular trafficking, the inhibition of COPZ1 in COPZ2-defficient tumor cells could cause Golgi apparatus collapse, block autophagy, and induce apoptosis in both proliferating and dormant cells. This suggests that the COPZ1 knockdown may suppress tumor growth selectively, making it a promising cancer therapy target. We used molecular docking, synthesis and cell biology to prove our hypothesis. To obtain the 3D structure of COPZ2 for in silico studies purpose, a homology modeling was performed using the amino acids sequence. A set of 84 molecules were submitted to molecular docking, and 4 compounds containing the active metabolite 4-aminoantipyrine and enedione fragment were selected for synthesis and in vitro evaluation. The selection was based on the interactions between the inhibitor and the amino acids within the binding site of the enzyme. Interestingly, the selected 1-4 compounds showed cellular growth inhibition of MIA PaCa-2 and AsPC-1 cell lines, but not for normal cell line. Our new drug prototypes based on 4-aminoantipyrine and enedione moieties showed quite good anti-cancer properties, therefore deserving to be considered in further studies with the aim of understanding the role of COPZ1 in tumor development, as a target for selective treatment. Citation Format: Allana Cristina F. Martins, Barbara M. Barbosa, Bretton Badenoch, Roberto S. Gomes. Design, synthesis, and in vitro evaluation of enedione derivatives as promising selective COPZ1 inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B051.
Abstract IA017: The role of vitamin D receptor agonists in the treatment of pancreatic adenocarcinoma
Authors: Kimberly Perez
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is composed of multiple cell types and a dense extracellular matrix that may support cancer cell proliferation and impede chemotherapy delivery. Cancer-associated fibroblasts (CAF’s) in the tumor microenvironment secrete pro-inflammatory factors and components of the extracellular matrix. In PC laboratory models, engagement of the vitamin D receptor (VDR) by VDR agonists shifts CAFs toward a more quiescent phenotype with reduced tumor growth and improved chemotherapy penetration. In this talk, I will review our understanding of the role of the VDR in PDAC, including the proposed mechanisms of growth inhibition, transcriptional profile changes in VDR agonist-treated tumors, and the impact on the immune tumor environment in VDR agonist-treated tumors. I will present the preliminary results of the safety run-in of a two-stage randomized phase 2 study (NCT03520790) evaluating the clinical impact of paricalcitol, a synthetic VDR agonist, when given with standard systemic chemotherapy of gemcitabine and nab-paclitaxel in previously untreated patients with metastatic PDAC. In the run-in stage, 36 patients were randomized 1:1:1 to gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) given 3 weeks on and 1 week off in addition to: paricalcitol 75 mcg IV weekly, paricalcitol 16 mg oral daily, or placebo oral daily. Lastly, I will present the preliminary analysis of the pre-treatment and on-treatment (after 6-8 weeks of therapy) tissue biopsies taken from patients participating in this study, highlighting the results of whole transcriptome sequencing and multiplex spatial analyses used to characterize VDR signaling activity and the tumor microenvironment. Citation Format: Kimberly Perez. The role of vitamin D receptor agonists in the treatment of pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA017.
Abstract C029: Chemotherapy backbone alters the mechanism of action of TGFb blockade in pancreatic cancer
Authors: Li Qiang, Lestat Ali, Meggie Hoffman, Jaime Ivan Castillo Silva, Patrick Lenehan, Elisa Bello, Marc Pelletier, Viviana Cremasco, Stephanie Dougan
Journal: Cancer Research (2022)

Abstract TGFβ plays a critical role in promoting pancreatic tumor progression, attenuating CD8 T cell proliferation and cytokine production, enhancing the differentiation of myofibroblasts and the deposition of extracellular matrix. However, single agent TGFβ blockade has shown limited efficacy in mouse models of pancreatic cancer. Here we showed that in combination with chemotherapy, using either gemcitabine/n(ab)-paclitaxel or FOLFIRINOX, neutralization of TGFβ can reduce tumor burden in the poorly immunogenic 6694c2 orthotopic pancreatic cancer mouse model, without affecting the metastatic rate of cancer cells. As expected, anti-TGFβ with combination chemotherapy significantly increased the mean survival time of the orthotopic mouse models. Surprisingly, the efficacy of both combinational therapies is not dependent on CD8 T cells in either immunogenic or non-immunogenic models, as CD8 depleted or RAG2 knockout mice are responsive to the treatments to similar levels. Instead, comparing to chemotherapy single treatment, in the presence of TGFβ blocking antibody, tumor cells are more vulnerable to chemotherapy-induced cell death, both in vitro and in vivo. Recent studies from Raghavan et al. demonstrated that the plasticity of the classical and basal lineage of pancreatic cancer can be regulated by TGFβ ligand. Consistently, here we show that single-cell analysis and limited bulk RNAseq on tumor cells sorted ex vivo revealed 6694c2 tumor cells treated with TGFβ blockade maintain classical lineage, the state of pancreatic cancer with more sensitivity to chemotherapy and better prognosis. FOLFIRINOX treatments have largely modified tumor stromal landscape, with a unique CAF population presented expressing high levels of PTX3, which further verified by immunohistochemistry. This study provides the scientific rationale for the evaluation of TGFβ with both chemotherapy backbone in the clinical setting, as well as supports the concept of plasticity of pancreatic cancer cell state and plasticity of stromal cell landscape in tumors, providing foundations for future investigations on the mechanisms of TGFβ with different chemotherapy backbone in regulating the crosstalk among fibroblast subsets, immune cells and pancreatic cancer cells. Citation Format: Li Qiang, Lestat Ali, Meggie Hoffman, Jaime Ivan Castillo Silva, Patrick Lenehan, Elisa Bello, Marc Pelletier, Viviana Cremasco, Stephanie Dougan. Chemotherapy backbone alters the mechanism of action of TGFb blockade in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C029.